The Section on Geriatric Psychiatry has focused on the pharmacologic modeling and treatment of memory disorders in the elderly as well as the underlying mechanisms of brain degeneration in Alzheimer's Disease (AD). Because the acetylcholine system is thought to be central in facilitating new learning and memory in humans, the Section had previously studied the effects of the central cholinergic antagonist, scopolamine, and found increased sensitivity in older normals which mimicked some but not all the memory difficulties of AD. Most recently, the cholinergic model has now been modulated with the acute doses of serotonergic agents, ondansetron and m-chlorophenylpiperazine (m-CPP). In these studies, the memory effects of scopolamine were exacerbated by m-CPP, a mixed serotonergic agonist-antagonist but essentially unaltered by a fixed dose of the 5-HT3 antagonist ondansetron. In a longer-term study utilizing the single photon emission computerized tomography (SPECT) neuroimaging technique, Alzheimer patients and elderly controls have been tested for cerebral perfusion and muscarinic receptor labeling both before and after three weeks of exposure to the antimuscarinic, scopolamine. These experiments have suggested differential upregulation responses to chronic cholinergic blockade across groups and have resulted in a follow-up therapeutic trial now in progress. In collaboration with the Unit on Neuroimaging, the Section has also continued its studies of blood flow patterns and associative memory effects following neuropharmacologic agents such as scopolamine and lorazepam. From a basic science perspective, progress has been made in understanding some of the normal physiologic roles of beta-amyloid in humans. Specifically, beta-amyloid has been found to increase tyrosine phosphorylation and cytosolic calcium when tested in vitro at physiologic levels. Furthermore, there is evidence that one of the genetic vulnerability markers of AD, APOE, may have variable effects in the regulation of amyloid precursor protein secretion. Further characterization of these physiologic roles may lead to novel therapeutic approaches or a rational strategy for the stratification of responders and non-responders in current clinical trials.